We seek to understand the interactions between Human noroviruses (HuNoVs) and their Histo-blood group antigen (HBGA) receptors in the attachment/penetration into host cells and potentially triggering conformational dynamics of the viral capsid and genome release in the early stage of viral infection. HuNoVs in the Caliciviridae family are the major cause of nonbacterial gastroenteritis worldwide. The highly contagious HuNoVs can rapidly spread among the population through contaminated food, water and person-to-person contact in confined spaces, such as cruises, hotels, schools, hospitals and other long-term health care facilities. There are approximately 21 million cases of infection in ~1,500 HuNoVs outbreaks in the United States annually, which causes severe economic loss to society and threatens human health. Despite this serious public health concern, knowledge about the infection mechanism and pathogenesis of HuNoVs is limited due to the lack of a permissive cell line. Our past decade studies showed a strong association of HBGAs as a susceptibility factor in NoV infection, and therefore further studies to seek direct evidence on HBGAs as a receptor of NoVs are necessary. In this R01 application, we will use the recently discovered primate Tulane virus (TV) as the model system to fulfill our goals because of its close genetic and structural similarities to HuNoVs, the availability of an established cultivation system, and the fact that TV also utilizes HBGAs as receptors. We will first test the HBGA requirement in TV infection in cell cultures by performing blocking or inhibition experiments using HBGA-specific blocking reagents. We also will study the roles of HBGAs in the attachment and/or penetration of TV entry into host cells. Furthermore, we will test a novel hypothesis of HBGA-triggered dynamic change of TV capsid on viral genome release to initiate infection. This hypothesis is based on our recent observation of conformational changes of TV following interaction with HBGAs. Finally, we will validate these findings using a reverse genetic system of TV by mutagenesis studies in attempt to determine the hot spots in the capsid protein responsible for these interactions. We also aim to develop the TV culture system into a useful surrogate for antiviral screening/evaluation against HuNoVs. The proposed studies in this application will be performed by collaboration between two research teams on structural biology (Wen Jiang, PI) and molecular virology (Xi Jiang, co-PI) with an excellent collaboration track record in the past. We are confident that we will make a rapid progress in fulfilling our aims.